9 Pain and anaesthesia
Basic concepts
Pain, which may be acute or chronic, is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience, as there are currently no means of accurately and objectively assessing the degree of pain a patient is experiencing.
An analgesic drug is one that effectively removes (or at least lessens) the sensation of pain. The principles of pain relief are:
Pain perception
Pain perception is best viewed as a three-stage process – activation of nociceptors, followed by the transmission and onward passage of pain information.
Activation of nociceptors in the peripheral tissues
Noxious thermal, chemical or mechanical stimuli can trigger the firing of primary afferent fibres (type C/Aδ), through the activation of nociceptors (pain-specific receptors) in the peripheral tissues (Fig. 9.2).

Fig. 9.2 Nociceptive pathways and sites of opioid action. (1) Activation of nociceptors in the peripheral tissues; (2) transmission of pain information; (3) onward passage of pain information to higher centres. (5-HT, 5-hydroxytryptamine (serotonin); Glu, glutamate; NA, noradrenaline; Sub P, substance P.)
Transmission of pain information
Transmission of pain information from the periphery to the dorsal horn of the spinal cord is inhibited or amplified by a combination of local (spinal) neuronal circuits and descending tracts from higher brain centres. This constitutes the ‘gate-control mechanism’. In the gate-control mechanism:
Onward passage of pain information
The onward passage of pain information is via the spinothalamic tract, to the higher centres of the brain. The higher centres of the brain coordinate the cognitive and emotional aspects of pain and control appropriate reactions. Opioid peptide release in both the spinal cord and the brainstem can reduce the activity of the dorsal horn relay neurons and cause analgesia (Fig. 9.2).
Opioid receptors
All opioids, whether endogenous peptides, naturally occurring drugs, or chemically synthesized drugs, interact with specific opioid receptors to produce their pharmacological effects.
Drugs interact with opioid receptors as either full agonists, partial agonists, mixed agonists (full agonists on one opioid receptor but partial agonists on another) or as antagonists. Opioid analgesics are agonists.
There are three major opioid receptor subtypes: μ, δ and κ. The existence of a fourth receptor(s) remains controversial.
Opioid receptor activation has an inhibitory effect on synapses in the central nervous system (CNS) and in the gut (Fig. 9.3).
Secondary-messenger systems associated with opioid receptor activity include:
Activation of all opioid receptors by endogenous or exogenous opioids results in:
Endogenous opioids
Physiologically, the CNS has its own ‘endogenous opioids’ that are the natural ligands for opioid receptors. There are three main families of endogenous opioid peptides occurring naturally in the CNS:
They are derived from three separate gene products (precursor molecules), but all possess homology at their amino end.
The expression and anatomical distribution of the products of these three precursor molecules within the CNS is varied, and each has a distinct range of affinities for the different types of opioid receptor (Fig. 9.4).
Though it is known that the endogenous opioids possess analgesic activity, their precise function is poorly defined. They are not used therapeutically.
Mrs Moore is a 60-year-old patient with advanced breast cancer who is receiving chemotherapy. She suffers with bone pain due to metastases. She has been on several analgesics for the pain since its onset, including non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs were effective to start off with, however the pain sharply increased in severity over the following months and so a decision was made to give her co-proxamol. Co-proxamol is an example of a compound analgesic, containing dextropropoxyphene and paracetamol. Compound analgesics contain both an opioid and a non-opioid. Co-proxamol was more effective in controlling the pain and she was able to continue doing more of the daily activities she used to do, until now. She has increasingly been feeling the pain and is suffering terribly. Review of her pain management and symptoms is taken and she is put on regular morphine as part of her palliative care management.
Opioid analgesic drugs
Opioid analgesics are drugs, either naturally occurring (e.g. morphine) or chemically synthesized, that interact with specific opioid receptors to produce the pharmacological effect of analgesia.
Mechanism of action
Opioid analgesic drugs work by agonist action at opioid receptors (see above).
The sense of euphoria produced by strong opioids contributes to their analgesic activity by helping to reduce the anxiety and stress associated with pain. This effect also accounts for the illicit use of these drugs.
Route of administration
Oral, rectal, intravenous, intramuscular, transdermal and transmucosal (as lozenges).
Oral absorption is irregular and incomplete, necessitating larger doses; 70% is removed by first-pass hepatic metabolism. Fentanyl is available in a transdermal drug delivery system as a self-adhesive patch, which is changed every 72 hours. Transdermal fentanyl is particularly useful in patients prone to nausea, sedation or severe constipation with morphine. Morphine is the drug of choice for severe nociceptive pain.
Indications
Strong opioids (Fig. 9.5) are used in moderate to severe pain, particularly visceral, postoperative or cancer-related; in myocardial infarction and acute pulmonary oedema; and in perioperative analgesia (p. 146).
Weak opioids (Fig. 9.5) are used in the relief of ‘mild to moderate’ pain, as antitussives (Ch. 3) and as antidiarrhoeal agents (Ch. 8), taking advantage of these ‘side-effects’ of opioid analgesics.
Contraindications
Opioid analgesics should not be given to people in acute respiratory depression, with acute alcoholism, at risk of paralytic ileus, and with head injuries prior to neurological assessment (interferes with assessment of the level of consciousness).
Adverse effects
Opioid analgesics share many side-effects. These can be subdivided into central adverse actions and peripheral adverse actions.
Central adverse actions include the following:
Peripheral adverse actions include the following:
Adverse effects of opioids tend to limit the dose that can be given, and the level of analgesia that can be maintained. The most serious of all these effects is respiratory depression, which is the most common cause of death from opioid overdose.
Constipation and nausea are also common problems and clinically it is common to co-administer laxatives and an antiemetic (Ch. 8).
Tolerance and dependence
Tolerance to opioid analgesics can be detected within 24–48 hours from the onset of administration, and it results in increased doses of the drug being needed to achieve the same clinical effect.
Dependence involves μ receptors and is both physical and psychological in nature and is discussed in Chapter 5. If physical dependence develops, it is characterized by a definite withdrawal syndrome following cessation of drug treatment. This syndrome comprises a complex mixture of irritable, and sometimes aggressive, behaviour combined with extremely unpleasant autonomic symptoms such as fever, sweating, yawning and pupillary dilatation. The withdrawal syndrome is relieved by the administration of μ receptor agonists, and worsened by the administration of μ receptor antagonists.
In the clinical context, especially in terminal care, where tolerance and dependence can be monitored, they are not inevitably problematic. However, the fear of tolerance and dependence often leads to over-caution in the use of opioid analgesics, and inadequate pain control in some patients.
Therapeutic notes
Strong opioid analgesics include morphine, diamorphine (heroin), phenazocine, pethidine, buprenorphine and nalbuphine:
Weak opioid analgesics include pentazocine, codeine, dihydrocodeine and dextropropoxyphene:
Opioid antagonists
Examples of opioid antagonists include naloxone and naltrexone.
Mechanism of action
These drugs act by specific antagonism at opioid receptors: μ, δ and κ receptors are blocked more or less equally. They block the actions of endogenous opioids as well as of morphine-like drugs.
Naloxone is short acting (half-life: 2–4 hours) while naltrexone is long acting (half-life: 10 hours).
Indications
Opioid antagonists are given to reverse opioid-induced analgesia and respiratory depression rapidly, mainly after overdose, or to improve breathing in newborn babies who have been affected by opioids given to the mother.

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